The advantages of ultrasound scanning, including low cost, wide availability and high patient-acceptance, makes ultrasound an attractive modality for CA screening and staging. However, the detectability of liver metastases by ultrasound B-scan imaging is less than ideal, in part because of the variability in tumor echogenicity relative to liver parenchyma. A contrast agent which increases the parenchymal echogenicity, but not tumor echogenicity, would significantly improve the ability of ultrasound to detect liver metastases and to monitor their response, to therapy. In our first grant period, we evaluated the contrast enhancement of liver by solid, micron size particles of iodipamide ethyl ester (IDE). These particles are biocompatible, are accumulated in Kupffer cells in the liver, and are eliminated in one to two days. Because these particles are dense, (2.4 g/cm3), they act as scatterers and increase the echogenicity of liver, but not the echogenicity of tumors which lack Kupffer cells . Because of the iodine in IDE, the particles also serve, as an x-ray CT contrast agent. In our recent experiments, we found that IDE at safe doses could raise the echogenicity of normal rabbit liver by 3dB, a useful and significant increase in backscatter. This enabled the detection of small (7 mm) VX2 tumors, which were otherwise isoechoic and undetectable in rabbit livers using ultrasound B-scan imaging. Furthermore, we found that the Kupffer cells near the portal triads acquired much of the IDE, creating a lobular zonal pattern of deposition which enhanced the ultrasound backscatter. In the next grant period, we will quantify the lobular zonal pattern of IDE acquisition by Kupffer cells and attempt to modify the zonal pattern, using DDE particles coated with substances designed to activate different receptors on the Kupffer cells. Furthermore, we will evaluate a new, hybrid particle-bubble agent that was recently invented. This new formulation stabilizes gas in hydrophobic crevices, resulting in sustained echogenicity which is insensitive to ambient pressures, a trait lacking in commercially developed bubble agents. The new formulations offer, for the first time, the possibility of introducing highly echogenic gas into the Kupffer cells of the liver, producing liver contrast in an elegant and efficacious manner. This research should lead to a better understanding of ultrasound backscatter enhancement and possibly a liver contrast agent which could be clinically useful for both ultrasound and CT.